Geographical distribution gradients of the major PKU mutations and the linked haplotypes

Summary Analysis of 81 phenylketonuria families from Bulgaria, Lithuania and eastern Germany demonstrated a high frequency of haplotype 2 and the associated Arg⁴⁰⁸ Trp⁴⁰⁸ substitution. Haplotype 3 and the splicing mutation in intron 12 are rare or absent in the groups studies. Pooling the data on European populations suggests a Balto-Slavic origin of the defect in codon 408 of the phenylalanine hydroxylase gene and a geographical gradient in the distribution of both major PKU mutations which may contribute to the higher incidence of classic PKU in northern Europeans.     

Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay-Lac-St-Jean.

Hereditary tyrosinemia type I is an autosomal recessive disorder that was recognized in Saguenay-Lac-St-Jean (SLSJ) (Quebec) in 1967. Ninety-eight tyrosinemic children, including some of the 113 children born in the SLSJ region, have been screened by the Quebec Network of Genetic Medicine in the whole province since 1970. The geographical distribution of the 98 children screened showed the majority of them to have been born in the northeastern part of Quebec. The prevalence at birth was estimated at 1/1,846 live borns, and the carrier rate was estimated at 1/20 inhabitants in the SLSJ region. Three control groups matched to the tyrosinemic obligate-carrier couples were generated using the population register of the SLSJ region kept at SOREP. The mean coefficient of inbreeding was only slightly elevated in the tyrosinemic group compared with the control groups and was due to remote consanguinity. The mean kinship coefficient was 2.3 times higher in the tyrosinemic group than in the control groups. In the SLSJ region the places of origin of the tyrosinemic children and their parents did not show a clustered nonuniform distribution. Endogamy was not found to be higher in the tyrosinemic group than in the control groups. All these results support both the hypothesis of a founder effect for tyrosinemia and a high gene frequency in northeastern Quebec.     

Analysis of the association of HLA-DQ1 alleles with mutation of the 21-hydroxylase gene in patients with congenital adrenal hyperplasia

In 96 patients with congenital adrenal hyperplasia (CAH) and 50 healthy donors from northwestern Russia the distribution of the HLA-DQA1 alleles and the mutation spectrum and frequency at the CYP21B gene were examined. In the patients with nonclassical (NC) CAH, the distribution of the HLA-DQA1 polymorphic alleles was similar to that in the population sample. In the patients with the salt-wasting form of the disease a statistically significant decrease of the *0401 or *501 major allele frequency was observed. The prevalence of certain HLA-DQA1 genotypes, namely, HLA5, HLA3, and HLA4, was observed in the patients with the NC, salt-wasting (SW), and simple virilizing CAH, respectively. Each clinical group was characterized by a specific spectrum of clinically valuable mutations. An association between the CYP21B mutations most frequently found in case of SW and SV CAH (delB, I2splice, and I172N) and certain HLA-DQA1 alleles was demonstrated. The necessity of more precise clinical diagnostics of the NC CAH cases along with detailed examination of this group for determination of the major mutations typical of the NC CAH cases from northwestern Russia is discussed.     

The distribution of the Hb Constant Spring gene in Southeast Asian populations

Summary The distribution of the hemoglobin Constant Spring (Hb CS) gene in eight populations in Southeast Asia (including Assam) was determined using oligonucleotide hybridization. Hb CS was absent in two Assamese populations with a high prevalence of Hb E. The Hb CS gene frequency was 0.033 in northern Thailand and near 0.01 in central Thailand and Cambodia. High frequencies, between 0.05 and 0.06, were observed in northeastern Thailand. The present data and a similar study in Laotians suggest that the Lao-speaking populations of the Mekong River basin in northeastern Thailand and Laos have the highest frequencies of the Hb CS gene in Southeast Asia.     

Population Genetics of Indigenous Quercus robur L. Populations and of Derived Half‐Sib Families has Implications for the Reproductive Management of the Species

Abstract: In the Netherlands indigenous Quercus robur L. populations are rare and have been maintained as patches in ancient woodland. For adequate conservation of these populations, information about genetic variation and population structure is necessary. In order to assess the genetic variation and structure of these populations, microsatellite polymorphisms were studied in two autochthonous populations. These two populations differed slightly for their gene diversity, which was as high as was observed for Q. robur populations in France and Germany. For reforestation purposes there is an interest in the genetic variation of a half‐sib family harvested from one tree. The gene diversity of the two studied half‐sib families ‐ obtained from a forest and an urban area ‐ was similar, but relatively low. This indicates that, for reforestation purposes, seeds should be harvested from many different trees in order to obtain a population with a genetic variation as high as was observed for an autochthonous population.     

Future developments in phenylketonuria

Treatment of classical phenylketonuria (PKU) is very good, but problems still exist in regard to the duration of treatment and a means of ensuring that all women with PKU recommence dietary treatment before becoming pregnant. A 'one-shot' cure of the disease remains desirable and may become available in the more distant future by somatic cell gene therapy. Insertion of a normal gene or correction of the defective gene at the normal site in the chromosome and in liver cells is likely to be necessary both technically and ethically. Prevention by prenatal diagnosis is not widely accepted in Australia and is likely to have little effect on the frequency of the disease.     

PKU in Slovakia: mutation screening and haplotype analysis

The restriction fragment length polymorphism haplotypes and seven common mutations in the phenylalanine hydroxylase gene were analysed in 49 unrelated Slovak phenylketonuria (PKU) families of Caucasian origin. The predominant mutation in this population sample is R408W, with a frequency of 45.9%. In addition, four other mutations have been identified at relatively high frequencies: IVS12nt1, 10.2%; R158Q, 7.1%; R261Q, 7.1%; R252W, 2.0%. The mutation-haplotype associations correspond to those described in other European populations. The high proportion of mutations (72.4%) amenable to simple rapid detection based on the polymerase chain reaction provides a good basis for direct DNA-diagnosis of PKU in the Slovak population.     

Population genetics of hereditary hemochromatosis in Saguenay Lac-Saint-Jean (Quebec, Canada).

Hereditary hemochromatosis (HH) is an autosomal recessive disorder that has a high prevalence in Caucasian populations. Based on HLA typing in 18 families, the gene frequency was estimated 0.12. The homozygote frequency was 0.014 and the heterozygote frequency was 0.21 in Saguenay Lac-Saint-Jean (SLSJ), a geographically isolated region of northeastern Quebec. The genealogical reconstruction showed that 15 of the 57 obligate carriers of the HH gene could be traced back to a unique ancestor in the 18th century. The mean coefficients of inbreeding and kinship were 17 and 15 times, respectively, higher in the HH group than in three control groups. The values of both coefficients were much higher than those found in other HH populations and in most of the other recessive disorders prevalent in SLSJ.     

Molecular genetics of phenylketonuria in Orientals: linkage disequilibrium between a termination mutation and haplotype 4 of the phenylalanine hydroxylase gene.

Phenylketonuria (PKU) is a common metabolic disorder among Chinese, with a prevalence of about 1 in 16,500 births. This frequency is very similar to that among Caucasians. Individual exons of the phenylalanine hydroxylase (PAH) gene with flanking introns were amplified by polymerase chain reaction and cloned into M13 for sequence analysis. An Arg111-to-Ter111 mutation has been identified in exon 3 of the PAH gene in a Chinese PKU patient. The mutation is in linkage disequilibrium with the mutant haplotype 4 alleles which are the most prevalent haplotype among the Orientals. The mutation accounts for about 10% of the Chinese PKU alleles and is absent from the Caucasians, demonstrating that independent mutational events have occurred in the PAH locus after racial divergence.     

Phenylketonuria in Spain: RFLP haplotypes and linked mutations

In order to investigate the molecular basis of phenylketonuria (PKU) in Spain, we analyzed the restriction fragment length polymorphism (RFLP) haplotypes and common mutations in the phenylalanine hydroxylase (PAH) gene in 32 unrelated Spanish PKU families. The distribution of RFLP haplotypes differs from that of northern Europe. Mutant haplotypes 2 and 3 were completely absent in our sample. Approximately 65% of the mutant alleles are confined to three RFLP haplotypes, namely haplotypes 1, 6 and 9, also frequently found in other Mediterranean populations. We screened for previously described PKU mutations using the polymerase chain reaction and allele-specific oligonucleotides, and found IVS10,165T, E280K and P281L as the major mutations, representing 41% of the PKU alleles. Other mutations found were Y414C, and a new one, P244L. Mutations R408W and IVS12, prevalent in northern Europe, as well as others present in southern European populations (R252W, R261Q, L249F) were not detected in our sample. Our results reveal the genetic heterogeneity present in the Spanish PKU population, which shows similarities to others of Mediterranean origin.     

Effect of maternal genetic heterozygosity]

The obstetrics histories of all the pregnances were studied, including the deliveries and abortions, the perinatal mortality of fetuses and the frequency of congenital malformations among newborns in 239 repeatedly pregnant women heterozygous for the gene of phenylketonuria (PKU), 40 women with the latent form of diabetes mellitus (LDM) and 96 women heterozygous for Dushenne's myopathy (MD). It was established that the frequency of women suffering from spontaneous abortions (SA) was increased as well as the SA frequency among all the pregnancies with natural results in heterozygotes for the PKU gene; it was also established that the frequency of stillborns and of the early mortality of newborns was considerably higher among women with LDM. In both these groups the frequency of congenital malformations among the newborns was also relatively high. In women heterozygous for the PKU gene the pathogenic effect was realized only during the first three months of pregnancy, while in women with LDM it was realized through all the period of pregnancy. The heterozygosity of women for MD proved not to be pathogenic for the progeny. Possible mechanisms realizing the effect of heterozygosity of women for the abovementioned recessive genes during pregnancy are discussed.     

基于125个地区的中国藓类植物区系的定量分析

系统收集了我国125个地区的藓类植物区系资料,统计了种和属在这些地区的分布频度。以藓类种数超过100的73个地区为研究对象,以科所含的种数为指标,应用除趋势对应分析和模糊均值聚类基础上的主坐标排序,对我国藓类植物区系的区域分化特点进行了定量分析。结果显示,随着分布频度增加,种和属数均呈指数式下降,绝大部分的种和属仅在极少数地区有记录。根据藓类植物的区系组成,73个地区可分成5组：第1组涉及华东、华中和西南的12个地区;第2组包括西北、华北为主的16个地区;第3组为人为干扰强烈的长三角等15个地区;第4组包括以华南为主的热带、南亚热带区域的19个山地;第5组包括西北、东北和西南的11个温带或高海拔山地。研究结果表明我国藓类区系报道在种类鉴定中可能存在比较普遍的误定现象,从而造成绝大部分种类局限于狭窄地理区域的假象。     

云南师宗白背飞虱前期迁入种群的虫源地分布与降落机制

通过对1990—2012年云南省师宗县4—5月出现的白背飞虱灯诱高峰日进行轨迹模拟以及降虫高峰日的风场分析,得到以下结果:4月下旬,师宗上空盛行西风,白背飞虱虫源主要来自缅甸东北部,部分来自越南北部和金三角地区;5月份,西南风为盛行风向,其中上中旬的虫源地主要分布在越南西北部、老挝北部和滇西南,缅甸东北部可提供部分虫源;下旬则主要分布在滇西南,部分虫源来自越南西北部、老挝北部和缅甸东北部。对降虫高峰期的大气环流背景、峰日风温场、降雨等气象因子的分析结果表明,降水、风切变和气流垂直扰动是造成白背飞虱集中降落的主要因子。     

Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in European families with phenylketonuria (PKU)

DNA haplotype data from the phenylalanine hydroxylase (PAH) locus are available from a number of European populations as a result of RFLP testing for genetic counseling in families with phenylketonuria (PKU). We have analyzed data from Hungary and Czechoslovakia together with published data from five additional countries--Denmark, Switzerland, Scotland, Germany, and France--representing a broad geographic and ethnographic range. The data include 686 complete chromosomal haplotypes for eight RFLP sites assayed in 202 unrelated Caucasian families with PKU. Forty-six distinct RFLP haplotypes have been observed to date, 10 unique to PKU-bearing chromosomes, 12 unique to non-PKU chromosomes, and the remainder found in association with both types. Despite the large number of haplotypes observed (still much less than the theoretical maximum of 384), five haplotypes alone account for more than 76% of normal European chromosomes and four haplotypes alone account for more than 80% of PKU-bearing chromosomes. We evaluated the distribution of haplotypes and alleles within these populations and calculated pairwise disequilibrium values between RFLP sites and between these sites and a hypothetical PKU "locus." These are statistically significant differences between European populations in the frequencies of non-PKU chromosomal haplotypes (P = .025) and PKU chromosomal haplotypes (P much less than .001). Haplotype frequencies of the PKU and non-PKU chromosomes also differ significantly (P much less than .001. Disequilibrium values are consistent with the PAH physical map and support the molecular evidence for multiple, independent PKU mutations in Caucasians. However, the data do not support a single geographic origin for these mutations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic structure of kestrel populations and colonization of the Cape Verde archipelago

Genetic diversity and population structure were studied in eight populations of the kestrel Falco tinnunculus to identify the genetic consequences of spatial distribution and to infer the colonization patterns of the Cape Verde archipelago. We studied genetic differentiation and gene flow among seven island populations and one mainland population using nine microsatellite loci. Within the archipelago, differentiation was strong and genetic diversity and heterozygosity were low but variable among populations. Two subspecies F. tinnunculus neglectus on the northwestern islands and F. tinnunculus alexandri on all the other islands were identified as genetically distinct units. F. t. alexandri could be further separated into two groups on eastern and southern islands. Populations are probably founded by birds originating from the mainland. Immigration is more likely to the eastern and southern populations, whereas the northwestern islands with the lowest genetic diversity and highest differentiation are likely to exhibit fewer founding events by immigrants. The number of founding events on each island may depend not only on geographical distance to neighbouring populations, but also on directional immigration due to the northeastern trade winds. This may explain differences in genetic differentiation and diversity between populations and subspecies and may enable allopatric speciation.     

Comparison of small subunit ribosomal RNA gene and internal transcribed spacer sequences among isolates of the intranuclear microsporidian Nucleospora salmonis

Nucleospora salmonis is an intranuclear microsporidian associated with a proliferative disorder of the lymphoid cells of captive salmonid fish in the northwestern and northeastern regions of North America, in France, and in Chile. Newer diagnostic approaches have used the polymerase chain reaction (PCR) to detect the parasite in fish tissues. The target sequences for these assays lie in the small subunit ribosomal RNA (ssu rRNA) gene or internal transcribed spacer (ITS) as determined from N. salmonis from chinook salmon (Oncorhynchus tshawytscha) from the Pacific Northwest of North America. The lack of sequence data on parasites from diverse geographic origins and hosts led us to compare several isolates of N. salmonis. There was a high degree of similarity in the ssu rDNA sequences (> 98%) among all the isolates of N. salmonis examined, regardless of host or geographic origin. The greatest sequence differences were found between isolates from the Pacific regions of America. Isolates from Chile shared sequences with one or both geographic groups from North America. A similar distribution of sequence types was observed when ITS-1 sequences of selected isolates were analyzed. Sequence data from two N. salmonis-like isolates from marine non-salmonid fish showed one closely related and the second less closely related to N. salmonis isolates from salmonid fish. These results provide evidence for a homogeneous group of aquatic members of the genus Nucleospora found among salmonid fish (N. salmonis) that can be detected using diagnostic PCR assays with ssu rDNA target sequences. The presence of parasites related to N. salmonis among marine fish suggests a potentially broad host and geographic distribution of members of the family Enterocytozoonidae.     

Analysis of the Association between the HLA-DQA1 Alleles and the Steroid 21-Hydroxylase Gene Mutations in the Patients with Congenital Adrenal Hyperplasia

In 96 patients with congenital adrenal hyperplasia (CAH) and 50 healthy donors from northwestern Russia the distribution of the HLA-DQA1 alleles and the mutation spectrum and frequency at the CYP21B gene were examined. In the patients with nonclassical (NC) CAH, the distribution of the HLA-DQA1 polymorphic alleles was similar to that in the population sample. In the patients with the salt-wasting form of the disease a statistically significant decrease of the *0401 or *0501major allele frequency was observed. The prevalence of certain HLA-DQA1 genotypes, namely, HLA5, HLA3, and HLA4, was observed in the patients with the NC, salt-wasting (SW), and simple virilizing CAH, respectively. Each clinical group was characterized by a specific spectrum of clinically valuable mutations. An association between theCYP21B mutations most frequently found in case of SW and SV CAH (delB, I2splice, and I172N) and certain HLA-DQA1alleles was demonstrated. The necessity of more precise clinical diagnostics of the NC CAH cases along with detailed examination of this group for determination of the major mutations typical of the NC CAH cases from northwestern Russia is discussed.     

Mitochondrial DNA variations in patients with maternally inherited diabetes and deafness syndrome

Mitochondrial DNA (mtDNA) variants have been implicated in the pathogenesis of diabetes. A mutation in the tRNA leucine gene at position 3243 has been previously reported in mtDNA of maternally inherited diabetes and deafness (MIDD) patients. Because the true prevalence of the mitochondrial origin in diabetes may be underestimated, we searched for potentially diabetogenic anomalies of mtDNA in 9 patients highly suspected of mitochondrial diabetes selected on maternally inheritance and clinical features. In order to detect high levels of mutant DNA, the mtDNA of muscle sample of 2 patients was totally sequenced and the 22 tRNA genes and flanking sequences of 7 patients were analyzed. A new homoplasmic mutation at position 8381 was found in the ATPase 8 gene of mtDNA of a MIDD patient. The prevalence of three homoplasmic variations (G1888A, T4216G, A4917G) was significantly higher in the small group of MIDD patients compared to controls and other subjects groups. This study demonstrated in our patients sample the high frequency of homoplasmic variations, which could play a role by themselves or in combination, in the pathogenesis of diabetes.     

The spectrum of mutations and methods for their detection in the phenylalanine hydroxylase gene in phenylketonuria patients from the novosibirsk region

Phenylketonuria (PKU) is a widespread autosome recessive hereditary disease caused by a deficiency of the liver enzyme phenylalanine hydroxylase, which results in distortion of metabolism of phenylalanine and accumulation of toxic metabolites. The knowledge of molecular bases of PKU is of a high social importance as it enables phenotypic correction of the disease in the case of its early diagnostics. This disease is known to be associated with mutations in the phenylalanine hydroxylase gene, the distribution and mutation spectrum having pronounced ethnic and regional features. We studied the spectrum of mutations in the phenylalanine hydroxylase gene in a group of patients with PKU from the Novosibirsk region to reveal 10 missense point mutations, 1 mutation in the splice donor site, and 1 microdeletion. For these mutations, most widely distributed in the region, we used straightforward detection methods basing on the restriction fragment length polymorphism (RFLP), artificial constructed restriction sites (ACRS) PCR, and denaturing gradient gel electrophoresis (DGGE).     

Expression of calpastatin, minopontin, NIPSNAP1, rabaptin-5 and neuronatin in the phenylketonuria (PKU) mouse brain: possible role on cognitive defect seen in PKU

Phenylketonuria (PKU) is an inborn error of amino acid metabolism. Phenylalanine hydroxylase (PAH) deficiency results in accumulation of phenylalanine (Phe) in the brain and leads to pathophysiological abnormalities including cognitive defect, if Phe diet is not restricted. Neuronatin and 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) reportedly have role in memory. Therefore, gene expression was examined in the brain of mouse model for PKU. Microarray expression analysis revealed reduced expression of calpastatin, NIPSNAP 1, rabaptin-5 and minopontin genes and overexpression of neuronatin gene in the PKU mouse brain. Altered expression of these genes was further confirmed by one-step real time RT-PCR analysis. Western blot analysis of the mouse brain showed reduced levels of calpastatin and rabaptin-5 and higher amount of neuronatin in PKU compared to the wild type. These observations in the PKU mouse brain suggest that altered expression of these genes resulting in abnormal proteome. These changes in the PKU mouse brain are likely to contribute cognitive impairment seen in the PKU mouse, if documented also in patients with PKU.